The overall theme of this research is that transmural cellular and structural heterogeneities are important determinants of normal and pathologic cardiac function. We will investigate the significance of transmural heterogeneity with in-vivo experiments in the dog in conjunction with computational modeling approaches. We hypothesize that cellular and structural heterogeneities contribute to mechanical gradients in function across the wall of the heart. These mechanical gradients in function are known to be an important factor for proper cardiac function in the normal heart, and may play a role in mechanical dysfunction in the failing heart. In heart failure, techniques such as enhancing epicardial calcium dynamics and optimizing external pacing lead location will be used to enhance global ventricular performance by altering mechano-electric and cellular heterogeneities. The specific aims will address the following hypotheses: (1) Transmural cellular heterogeneity is a determinant of transmural mechanical function in the left ventricle. This will be tested in-vivo by altering cellular properties such as calcium handling and action potential duration differentially across the wall, and examining the changes in local mechanical function. We will also examine the role of altered activation sequence on regional synchrony of mechanics in the canine heart. (2) Transmural and regional variations of laminar sheet structure influence local shear strains and wall thickening. Novel findings suggest a different laminar structure near the endocardium, and a combination of model and experiment will elucidate the role of these heterogeneities, as well as the role of fiber dispersion, in local mechanical function. (3) Heterogeneities in structure and function affect transmural ventricular mechanics in chronic heart failure. In a dog model of heart failure we will alter local cellular function and examine improvements in regional and global mechanics. We will assess changes in tissue structure in the failing heart, and the significance of the changes. Ventricular pacing is used to increase cardiac output in the failing heart. We will test the hypothesis that minimizing the 'prestretch' tissue area can be used as an algorithm to select pacing sites which improve global and regional function in the failing heart.